Spinal Cord Injury

Drug Treatment

Three main categories of drug treatment for spinal cord injury:
anti-inflammatories, antioxidants, and anti-excitotoxins

Immediate
pharmaceutical intervention is essential to improve the chances of recovery for
patients of spinal cord injury.There are three main categories of drugs for these patients:
anti-inflammatories, antioxidants, and anti-excitotoxins. Anti-inflammatories
act against immune system responses, antioxidants prevent oxidation, and
anti-excitotoxins fight excitotoxicity.These three processes damage the spinal cord tissue, and are explained
in Secondary Damage.

Within each of
these three categories, a number of drugs exist.Methylprednisolone is the most prominent anti-inflammatory,
though it also acts as an antioxidant.Lazaroids are also antioxidants.Anti-excitotoxins include thyrotropin-releasing hormone, Sygen, and
calcium-channel blockers.Ongoing
research is being conducted to improve current drug therapies, as well as to
find new and more effective pharmaceutical options.

Inflammation
is a process that generally promotes the healing of an injury.It does so in part by delivering
additional immune cells and molecules to the injured site.Unfortunately, these inflammatory cells
produce free radicals, which modify molecules necessary for proper cell
function in the spinal cord.Free
radicals are chemical substances with an unpaired electron and therefore very
reactive.They can cause lipid
peroxidation, an irreversible chain reaction that damages neurons and blood
vessels cells by destroying their lipid bilayer (cell membrane).In the picture
to the right the red particles are oxygen free radicals, shown destroying the lipid
bilayer (Source:
http://www.lef.org/magazine/mag2006/jun2006_report_sod_01.htm).The section onSecondary Damageprovides
more information about the damaging effects of immune responses on the spinal
cord.

Because,
however, secondary damage occurs during the hours following the initial trauma,
anti-inflammatory therapy can help decrease the effects of an injury.Currently, the standard
anti-inflammatory given to patients who have just suffered a spinal cord injury
is methylprednisolone, a corticosteroid.Corticosteroids are synthetic versions of glucocorticoids, a family of
hormones involved in the regulation of immune responses.

First, it is
important to understand how corticosteroids work to reduce inflammation.Their natural counterparts,
glucocorticoids, bind to receptors located inside the cell nucleus.The hormone-receptor complex then acts
as a transcription factor, which controls the transcription of DNA.When bound to a receptor,
glucocorticoids promote the transcription of genes, or they very occasionally
suppress such transcription.The
figure below, from Basic Neurochemistry 6th Ed., illustrates this process.

The
anti-inflammatory actions of methylprednisolone are mediated through this type
of receptor interaction, and they include reducing the period and intensity of
inflammation, inhibiting white blood cells from recognizing foreign chemicals,
and preventing the destruction of pathogens.To have such protective effects,
corticosteroids must be given at very high doses; these doses also intensify
the harmful effects of glucocorticoids (discussed later) because such large
amounts of substance do no naturally occur.

Interesting,
though, is that the receptor-mediated anti-inflammatory actions of
methylprednisolone seem to be secondary to its role as a neuroprotective.Its greatest effects appear to result
specifically from its antioxidant action, specifically its ability to combat
lipid peroxidation.The healing
effects of this action are summarized in the flow chart below from Hall
(2003).Methylprednisolone
integrates itself into the structure of the lipid bilayer, making the cell
membrane more rigid and thus preventing the movement of lipid peroxyl radicals
within it.

Limitations
exist, however, to the effectiveness of methylprednisolone. First, to exert its neuroprotective
effects, it must be constantly administered intravenously in high doses of 30
mg/kg.Secondly, because lipid
peroxidation sets in quickly and can last at least from 24 to 48 hours,
immediate and continued treatment is necessary.

Risks must be
considered as well regarding methylprednisolone.Problems arise as a result of the high dose, and they are
most prominent in treatments extending beyond 24 hours, the time limit
determined by theSecond National
Spinal Cord Injury Study.Such
complications include pneumonias, pressure sores, bleeding in the
gastrointestinal system, and the formation of blood clots in veins.Concern has also arisen that the
current method of methylprednisolone treatment may cause myopathy, or muscle
weakness, and it is supported by a preliminary study by Qian, et al
(2004).

Other side
effects simply result from the fact that methylprednisolone is a
corticosteroid. For instance, there is a small margin of error between
effective and unsafe doses, as well as a small frame of time after the injury
for effective treatment to be initiated; beyond 8 hours, it is detrimental to
begin treatment because, ironically, the anti-peroxidation action of
methylprednisolone can slow down the removal of peroxidized lipids and thus
exacerbate the damage.Most
notable, though, is that corticosteroids may inhibit neuronal regeneration by
interfering with neurotrophins.The section on Regenerationhas more information on regenerative processes and neurotrophins.

However,
conflicting studies hinder our understanding of whether methylprednisolone
actually interferes with regeneration.Hayashi et al. (2000) reported
that the corticosteroid does prevent regenerative growth.On the other hand, a study by Nash et
al. (2002) investigated the effects of
methylprednisolone on the efficacy of transplanted ensheathing cells, which
promote axon growth in the central nervous system, and found that the
ensheathing cells still functioned properly.Cell transplant is one of several therapies currently being
studied and is explained more in Regeneration.

Methylprednisolone
is clearly a controversial method of treatment for acute spinal cord
injury.In fact, it has not been
approved in the United States for treatment of spinal cord injuries.Although it has many positives, it is
difficult to ignore the negatives.Though some current research is trying to determine exactly those pros
and cons, many scientists are working to develop safer and more effective
pharmaceutical treatments.

Because the
effectiveness of methylprednisolone is not notably due to glucocorticoid receptor-mediated
anti-inflammatory actions, and because dangers are associated with those
actions, researchers developed a family of antioxidants that also prevents
lipid peroxidation, but without the corticosteroid-related side effects.These drugs are known as lazaroids and
were created by modifying the methylprednisolone molecule.The chemical structures of
methylprednisolone and a lazaroid are shown below, adapted from Hall &
Springer (2004).

Lazaroids
work against lipid peroxidation in two ways.The first is by the same manner as methylprednisolone: they
incorporate themselves into the cell membrane and thereby stop the chain of
destructive reactions set off by peroxyl radicals.Their second mechanism of action is to scavenge peroxyl
radicals, stabilizing the molecules that set off the chain.

Tirilazad was
chosen to be developed for clinical trials.It was found to be as effective as a 24-hour treatment of
methylprednisolone when treatments were begun within three hours of injury.Additionally, research could find no
evidence that tirilazad has any side effects even after extended
administration, suggesting that it may be a safer option than
methylprednisolone in cases where therapy needs to continue after 48 hours.However, it is important keep in mind
that these results are not definitive.

It is also
important to note that the FDA has not approved tirilazad for spinal cord
injury treatment.This is due in
part to the fact that it has been tested only against another unapproved drug,
methylprednisolone.For tirilazad
to become a treatment option, it will have to be compared to placebo, which
will occur only if determined to be ethically appropriate.

Other lazaroids
too are under investigation.Compound U-74500A offers especially exciting possibilities since it is
in fact more effective than tirilazad.Iron radicals catalyze, or speed up, some peroxidation reactions;
U-74500A can interact with these iron radicals.In effect, it can remove not only the peroxyl radicals that
cause lipid peroxidation, but also the radicals that increase rate at which the
harmful process occurs.Tirilazad,
on the other hand, cannot interact with iron radicals.Lazaroids and other antioxidants will
continue to be investigated as important possible treatments of acute spinal
cord injury.

High dose
vitamin therapy has just recently begun, though the results of a preliminary
study by Liao and Song (2004) on high dose
vitamin C do not seem promising; they found that
while vitamin C effectively prevents lipid peroxidation, it does not do so and
well as methylprednisolone.Research regarding vitamin E is equally unfruitful; Koc et al. (1999) found that although it greatly reduced lipid
peroxidation, vitamin E was not as effective as either methylprednisolone or tirilazad.